JPS61267586A - Novel cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> is (COOH-substituted) lower alkyl; R<2>-R4 are H, OH, methoxy or acetoxy], its salt, or its ester. E X A M P L E : 7 - [ ( Z ) - 2 - ( 2 - A m i n o t h i a z o l - 4 - y l ) - 2 - m e t h o x yiminoacetamido]-3-(2-methyl-1,2,3,4,-teterahydro-2-isoquinolinium)met hyl-3-cephem-4-carboxylate. USE:A remedy and preventive against microbisms such as infectious diseases of the inspirator, urinary-tract infection, infectious diseases of obstetrics and gynecology, suppurative infectious diseases, surgical infectious diseases, etc. PREPARATION:A compound shown by the formula II [R<5> is H or amino-protecting group; R<6> is H or COOH-protecting group; R<7> is (substituted) lower alkyl; X is halogen or eliminated group; Y is S or SO] is reacted with an amine shown by the formula III (R<8>-R<10> are H, OH, methoxy, etc., R<11> is H or methyl) to give a compound shown by the formula IV, which is optionally methylated, reduced and deprotected.

Description

[Detailed description of the invention] The present invention relates to novel cephalosporin derivatives.

β-lactam antibiotics are selectively toxic only to bacteria;
Since it does not affect animal cells, it plays an important role in the prevention and treatment of bacterial infections as an antibiotic with few side effects. In particular, cephalosporin derivatives are generally stable against penicillinase, have a broad antibacterial spectrum (and are often used for the prevention and treatment of bacterial infections). New, more potent, broad-spectrum cephalosporin derivatives are needed for the treatment of refractory infections caused by non-glucose-fermenting Gram-negative bacilli such as Staphylococcus or resistant Pseudomonas aeruginosa and Acinetobacter Ichiban calcoaceticus. It is being

The present inventors have 2-(2-aminothiazol-4-yl)-2-substituted-oximinoacetyl as the side chain at position 7 and 2-methyl-1,2,3,4 at position 3. A novel cephem compound substituted with -tetrahydro-2-substituted isoquinolinium methyl was synthesized and found to have a broad and potent antibacterial spectrum.

The present invention is based on the general formula (wherein R1 is a linear or branched lower alkyl group which may be substituted with a carboxyl group, R2, R3 and R4 may be the same or different, and each is a hydrogen atom, a hydroxyl group, methoxy group or acetoxy group), its salt, or its physiologically hydrolyzable ester.

Cephalosporin derivatives having a quaternary ammonium salt structure are disclosed in, for example, JP-A-55-55690 and JP-A-55-59.
No. 196, No. 58-174687 and No. 58-198
Although it is described in Japanese Patent No. 490, the compound of formula (1) is a new compound having a chemical structure different from these derivatives. Formula I
The compound is effective not only against Gram-positive bacteria but also against Gram-negative bacteria, especially non-fermenting glucose such as Pseudomonas aeruginosa and Acinetobacter calcoaceticus.
Has a broad antibacterial spectrum.

Generally, the substitution at the oximino group can take the E or Z geometric isomeric structure, but the substitution at the oximino group contained in the 7-position acylamino moiety of the compound of formula I has the structure 2. Lower alkyl groups which may be substituted with carboxyl groups for the substituent R1 of the compound of formula I include, for example, methyl, ethyl, n-propyl, inpropyl, n-butyl, carboxymethyl. , 1-
Examples include carboxy-1-methylethyl group.

Compounds of formula I can be prepared by the method described below.

General formula (wherein R5 is a hydrogen atom or an amine protecting group, R6 is a hydrogen atom or a carboxyl protecting group, R7 is a linear or branched lower alkyl group that may be substituted with a protected carboxyl group, and X is a Halogen atom or leaving group, Y is S
or a salt thereof) represented by the general formula (wherein R8, R11 and RlG may be the same or different, each being a hydrogen atom, an optionally protected hydroxyl group, a methoxy group or an acetoxy group, all represents a hydrogen atom or a methyl group),
A compound represented by the general formula (in the formula, R5, R6, R7, R8, R9, RIG, R" and Y have the above-mentioned meanings, and xo represents an anion), which is methylated as necessary. And/or after reduction, the protecting group is removed (Method A).

A compound represented by the general formula e (wherein R6, R8, R9, R" and X have the above-mentioned meanings), a salt thereof, or a silyl compound thereof, ) to form a compound of the general formula (wherein R'', R6, R7, R8, R9, R'' and xo have the meanings given above), and then Remove the protecting group (Method B).

Examples of the amino protecting group for the compound of formula (1) and the substituent R5 of the carboxylic acid of formula (2) include trityl group, formyl group, chloroacetyl group, trifluoroacetyl group, t-
Examples include butoxycarbonyl group, trimethylsilyl group, t-butyldimethylsilyl group, and the like. Particularly preferred is a trityl group that can be easily removed by acid treatment. Substituent R6
Examples of carboxyl protecting groups for R7 and R7 include the following protecting groups. Lower alkyl groups such as t-butyl group, haloalkyl group such as 2,2.2-)lichloroethyl group, alkanoyloxyalkyl group such as acetoxymethyl group, propionyloxymethyl group, hivaloyloxymethyl group, 2-acetoxyethyl group, 2 - propionyloxyethyl group, etc., alkanesrunenyl alkyl group, such as mesylmethyl group, 2-mesylethyl group, etc., aralkyl group, such as hahenzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, phenethyl group, trityl group,
Alkylsilyl groups such as benzhydryl group, bis(4-methoxyphenyl)methyl group, 6,4-dimethoxybenzyl group, etc., such as trimethylsilyl group.

Particularly preferred are benzhydryl groups or t-butyl groups, which can be easily removed by acid treatment. Substituent X of the compound of formula ■
Examples of the halogen atom include chlorine, bromine, and iodine; examples of the leaving group include an acetoxy group, a trifluoroacetoxy group, a mesyl group, a methanesulfonyloxy group, a trifluoromethylsulfonyloxy group, a phenylsulfonyloxy group, Examples include p-tolylsulfonyloxy group. Bromine or iodine is particularly preferred.

As the reactive derivative of the carboxylic acid of formula (1), for example, acid halides, mixed acid anhydrides, active esters, etc. are used. The acid halide of a carboxylic acid of formula (2) can be obtained by reacting a carboxylic acid (Vl) with a halogenating agent. This acid halide forming reaction is carried out in inert solvents such as methylene chloride, chloroform, dichloroethane, benzene,
It is carried out in toluene etc. and mixtures thereof.

Examples of halogenating agents include thionyl chloride, phosphorus trichloride,
Phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, oxalyl chloride, phosgene, etc. are used. The amount of the halogenating agent used is 1 to 10 mol, preferably 1 to 1.5 mol, per 1 mol of carboxylic acid (■). Reaction temperature is -40 to +1
00°C, preferably -20 to +20°C.

The mixed acid anhydride of carboxylic acid of the formula (■) is carboxylic acid (V
It can be obtained by reacting 1) with alkyl chlorocarbonate, aliphatic carboxylic acid chloride, etc. The reaction is carried out in an inert solvent such as acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, benzene, ethyl acetate, dimethylformamide, etc. or mixtures thereof. This reaction is preferably carried out in the presence of a tertiary amine such as triethylamine or N-methylmorpholine. The reaction temperature is -30 to +20°C, preferably -15 to 100°C.
) with an N-hydroxy compound or a phenol compound. The reaction is carried out in an inert solvent such as acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate, dimethylformamide, etc. or mixtures thereof. Examples of N-hydroxy compounds include N-hydroxysuccinimide, N-hydroxyphthalimide, 1-
Examples of phenol compounds such as hydroxybenzotriazole include 4-ditrophenol, 2,4-dinitrophenol, trichlorophenol, and pentachlorophenol. This reaction is carried out using a condensing agent such as N,
- Preferably carried out in the presence of dicyclohexylcarbodiimide. The reaction temperature is -30 to +40°C, preferably -10 to +25°C.

The compound (2) in which the group Y is S is obtained by reacting a compound represented by the general formula (wherein R6 and Y have the above-mentioned meanings, and 2 represents a hydrogen atom or an acyl group) with a carboxylic acid of the formula (2). It can be obtained by acylation using a chemical derivative. Further, the compound of the formula (2) in which the group Y is SO can be obtained by oxidizing the compound (2) in which the group Y is S. The compound (2) in which the substituent X is iodine can be produced by reacting the compound (2) in which the substituent X is chlorine with sodium iodide.

The compound of formula V is a compound of formula (■) in which 2 is an acyl group, R
It can be obtained by reacting with an amine of formula (2) where " is a methyl group, followed by deacylation.

The compound of formula (1) can be easily produced from a compound represented by the general formula C00Rc' (in which R6 and 2 have the meanings described above). □When producing the compound of formula I by method A, first, Compound 2 is reacted with an amine of formula I in a solvent. As the solvent, for example, nonaqueous organic solvents such as methylene chloride, chloroform, ether, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, or mixtures thereof are used.

The amount of the amine of formula I to be used is:
The amount is 1 to 5 mol, preferably 1.5 to 2.5 mol. The reaction temperature is -60 to +65°C, preferably -20 to +5°C, and the reaction is completed in 0.2 to 10 hours.

When using amines of formula I in which the substituent R'' is a hydrogen atom, the product (IT) is reacted with methyl iodide. This methylation reaction can also be carried out in a solvent. A non-aqueous organic solvent is preferred.Product (m) may be used as is or isolated.The amount of methyl iodide used is preferably 1 to 60 mol per 1 mol of product (■). 6 to 15 moles.Reaction temperature is -30 to +3
The temperature is 5°C, and the reaction is completed in several hours to several days. When the product (IV) is added to excess methyl iodide and reacted at -20 DEG to +10 DEG C. in the absence of a solvent, the reaction is completed in 66 to 48 hours.

When using a compound of formula (IV) in which the group Y is S═O, the product (IV) can be prepared by a known method, such as Journal Organic Chemistry 65, 246o (1970), Synthesis 58 (1979) or Journal Chemical・
It is reduced by the method described in Research (81, 341 (1979), etc.).

For example, product (IV) may be combined with an inert organic solvent such as acetone, methylene chloride, chloroform, tetrahydrofuran,
Dissolve in ethyl acetate etc., add potassium iodide, -40 ~
Add 7 cetyl chloride dropwise at 0℃, -20~-10℃
Reduction can be achieved by reacting for 1 to 2 hours. The amount of potassium iodide used is 5.
-15 mol, preferably 8-10 mol. Removal of the protecting group from the compound thus obtained gives the compound of formula I.

The protecting group can be removed by appropriately selecting a commonly used method depending on the type of the protecting group.

A method using an acid is preferred, and examples of the acid include inorganic or organic acids such as dinic acid, trifluoroacetic acid, benzenesulfonic acid, para-toluenesulfonic acid, and hydrochloric acid, with trifluoroacetic acid being preferred. Note that when trifluoroacetic acid is used as the acid, the reaction is accelerated by adding anisole. Further, this reaction is preferably carried out in an inert solvent, for example, an organic solvent such as methylene chloride, ethylene chloride, benzene, or a mixed solvent thereof, particularly methylene chloride. The reaction temperature is not particularly limited, and depends on the chemical properties of the raw material compounds and reaction products, the type of protecting group,
It is preferable to select an appropriate method depending on the type of removal method, or to perform the removal under mild conditions such as cooling or heating.

When producing the compound of formula (1) by Method B, first the compound of formula V is reacted with the reactive derivative of the carboxylic acid of formula (2) in a solvent. The reaction is carried out in an inert solvent such as water, acetone,
It is carried out in dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, benzene, ethyl acetate, dimethylformamide, etc. or mixtures thereof. The amount of the reactive derivative of carboxylic acid (VI) used is 1 to 1.5 mol per mol of the compound of formula V. The reaction temperature is -40 to -40℃, preferably -20 to +30℃
It is. When using the acid chloride of carboxylic acid (Vl), it is preferable to react it in the presence of an alkali metal carbonate or an organic amine such as trimethylamine, triethylamine, N-methylmorpholine, etc.

After the reaction is complete, the product (2) is separated and the protecting group is removed in the same manner as in Method A to obtain the compound of formula I.

The compounds of formula I can be converted into salts or physiologically hydrolyzable esters in a conventional manner.

The salts of the compound of formula I are conventional pharmaceutically acceptable salts, such as alkali metals such as sodium, potassium, alkaline earth metals such as calcium, magnesium, N,N
'-Dibenzylethylenediamine, organic amines such as procaine, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, hydrobromic acid, acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid, malic acid, tartaric acid , (including salts of organic acids such as citric acid, organic sulfonic acids such as methanesulfonic acid, isethionic acid, and halatoluenesulfonic acid, and amino acids such as aspartic acid and glutamic acid. Physiologically hydrolyzable esters include: For example, alkanoyloxyalkyl esters such as acetoxymethyl ester, pivaloyloxymethyl, alkoxycarbonyloxyalkyl esters such as 1-(ethoxycarbonyloxy)-1-ethyl, 1-phthalidyl ester, 5-methyl-2- 5-Substituted-2-oxo-1,6-dioxo-4 such as oxo-1,6-dioxo-4-ylmethyl
-yl methyl esters and the like are preferred.

The minimum inhibitory concentration (MI) of the compounds of the present invention against various bacteria
C: mcg/ml) with cefotaxime and hisceftazidime as comparison compounds.
It was measured by the agar plate dilution method using a disk 9 agar (bacterial count: 106 CFU/ml). The results are shown in Tables 1 and 2 below.

The compounds of the present invention exhibited strong antibacterial activity against sensitive and resistant Gram-positive and Gram-negative bacteria, particularly Pseudomonas aeruginosa, Pseudomonas cepacia, Acinetobacter calcoaceticus, and the like.

Accordingly, the present invention further provides an antibacterial agent containing a compound of formula I or a salt thereof or a physiologically hydrolysable ester thereof as an active ingredient.

The compounds of the invention can be mixed with solid or liquid excipient carriers and used in the form of pharmaceutical preparations suitable for oral, parenteral or external administration. Pharmaceutical preparations include injections, liquid preparations such as syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories.

The above formulations may contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers and the like. For example, the injection may contain additives such as distilled water for injection, physiological saline, a solution such as Ringer's solution, and a preservative such as methyl paraoxenbenzoate and propyl paraoxybenzoate. Liquid preparations such as syrups and emulsions include nlubitol syrup, methylcellulose, glucose, L, 1. Sugar. Tubu, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, edible oil,
Tonsil oil, coconut oil.

In addition to oily esters, nrubitan monooleate, phlopylene glycol, chrycerin, ethyl alcohol, water, etc., it may also contain emulsifiers such as gum arabic, gelatin, lecithin, surfactants such as Tween and Span, and the like. Solid agents include lactose, sucrose, corn starch, calcium phosphate, magnesium stearate, talc, silicic acid, gum arabic, gelatin, nrubitol, tragacanth, polyvinylpyrrolidone, polyethylene glycol,
Sodium lauryl sulfate and the like are used. As bases for ointments and suppositories, for example, cacao butter, glycerides, polyethylene glycols, white petrolatum, etc. are used. A surfactant or an absorption enhancer may be contained if necessary.

Compound (I) of the present invention can be used to treat bacterial infections, such as respiratory infections.
It can be used for the treatment and prevention of urinary tract infections, obstetric and gynecological infections, purulent diseases, surgical infections, etc. The dosage varies depending on the age and condition of the patient, usually 1. ~
It can be used in the range of 1001 #/kg, but 5 to 5 per day.
Preferably, the dose is 60 ap/ky, divided into 2 to 4 doses.

Example 1 (A) Penthydryl 7-((Z)-2-methoxyimi/-2-(2-)ditylaminothiazol-4-yl)
acetamido)-3-(2-methyl-1,2,3,4-
Tetrahydro-2-inquinolinium) methyl-3-cephem-4-carboxylate ・Iodo salt: Benhydryl 7-C(Z)-2-methoxyimi/-2
-(2-)Dithylaminothiazol-4-yl)acetamide]-3-iodomethyl-3-cephem-4-carboxylate 311 (3°21 mmol) was suspended in diethyl ether 320- and 2-methyl- 1,2
,3,4-tetrahytroinquinoline 940rn9(6
, 38 mmol) and stirred for 15 minutes, the precipitate was collected and 2-methyl-1,2,3,4-tetrahydroisoquinoline 5oorn9 (3.4 mmol) was further added to solution F and stirred for 40 minutes. Afterwards, the precipitate was collected.

The above precipitates were combined and dried to obtain Δ2 and Δ of the title compound.
1.1 g of a mixture of 3 isomers was obtained.

(a7-[:(Z)-2-(2-aminothiazole-
4-yl)-2-methoxyiminoacetamide]-! 1
-(2-methyl-1,2,5,4-tetrahydro-2-
Inquinolinium) methyl-6-cephem-4-carboxylate: 1.11 of the mixture of d and d isomers obtained in (A) was dissolved in methylene chloride at 10 mA! and anisole i, i dissolved in TILl and water-cooled-5 trifluoroacetic acid 10 ml! was added dropwise, and the mixture was stirred at 15° C. for 3 hours. The reaction solution was concentrated under reduced pressure, 30 g of ethyl acetate and 20 g of water were added, the aqueous layer was separated and adsorbed on HP-20 (501 rLl), and then 50 g of ethyl acetate and 20 g of water were added.
% methanol, fractions containing the target compound were collected, concentrated under reduced pressure, and then lyophilized to obtain the target compound 501n9 (yield 2.9%).

Melting point 166°C (decomposed).

IR(KBr): 1765.1660.1610
．． 1530.1345.1035crn-' NMR (D20) δ: 2.80-5.40 (6H1m
), 4.0! +(!IH,S), 5.40 (IH
la, J=5.4 ) 5.87 (IH, a, , T
=5.4), 7.00 CIH,s), 7.3Cl~7
．． 45 (4H%m) Example 2 (A) Penthydryl 7-((Z)-2-methoxyimino-2-(2-)!J thylaminothiazol-4-yl)acetamidocy3-chloromethyl-6- Cephem
4-Carboxylate 1-oxide: Penthydryl 7-C(Z)-2-methoxyimino-2
2.5 g (2.97 mmol) of -(2-)ditylaminothiazol-4-yl)acetamide]-7rochloromethyl-3-cephem-4-carboxylate was dissolved in 25 ml of benzene and filtered with methanol under water cooling. benzoic acid 6
40rn9 (6.27 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate, washed with 5% acidic sodium sulfite aqueous solution and saturated saline, and dehydrated with anhydrous sodium sulfate.

Concentration under reduced pressure gave the title compound as an oil.

, (B) penthydryl 7-C(Z)-2-methoxyimino-2-(2-)ditylaminothiazol-4-yl)acetamide]-6-iodomethyl-6-cephem-
4-Carboxylate 1-oxide: Dissolve the oil obtained in (A) in acetone 5Q1111,
670 m9 (4.47 mmol) of sodium iodide was added and stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with 5% thiosulfate, water, and saturated brine, then dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oil. Ta.

(C) Penthydryl 7-C (Z+-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)
Acetamide]-3-(6,7-Simethoxy-2-methyl-1,2,6,4-tetrahydro-2-inquinolinium)methyl-6-cephem-4-carboxylate 1
-Oxide iodo salt: Dissolve the oil obtained in CB) in 20 ml of dimethylformamide and add 6,7-simethoxy-2-methyl-1,2,3
,4-tetrahydroisoquinoline 1.239 (5,95
The mixture was stirred at room temperature for 6 hours. The reaction solution was poured into ice water, extracted with methylene chloride, and washed successively with water, 5% aqueous acidic sodium sulfite solution, and saturated brine. The extract was dehydrated with anhydrous sulfuric acid (IJ), concentrated under reduced pressure, and the oily residue was solidified when treated with diethyl ether. This solid was separated and dried to obtain 2.6 g of powder (yield: 75.7%).

(D) Penthydryl 7-((Z)-2-methoxyimino-2-(2-)ditylaminothiazol-4-yl)acetamide)-6-(6,7-simethoxy 2-
Powder obtained with methyl-1,2,5,4-tetrahydro-2-inquinolinium)methyl-6-cephe (C) 2.6
9 (2.25 mmol) was dissolved in 40 g of acetone,
Add 3.8.9 (25.3 mmol) of sodium iodide to this, and add 0.85 ml of acetyl chloride at -30°C.
After dropping (11.85 mmol), -30 to -2
Stirred at 0'C for 1 hour and at -20 to -10C for 6 hours.

The reaction solution was added to an ice-cooled sodium metabisulfite aqueous solution, and the precipitate was washed with water. After dissolving this precipitate in methylene chloride and washing with water and saturated saline,
Ethyl ether was added to the oily residue obtained by dehydration with anhydrous sulfuric acid (IJ) and concentration under reduced pressure, which was solidified, dried several times, and obtained 21 g of powder (yield: 81.9%).

(E)7-1: (Z)-2-(2-aminothiazole-
4-yl)-2-methoxyiminoacetamide]-3-
(6,7-Simethoxy2-methyl-1,2゜3.4-
Tetrahydro-2-inquinolinium) methyl-3-cephem-4-carboxylate: (powder obtained by DJ2.
1 g (1.84 mmol) of methylene chloride 151 rL
15 ml of trifluoroacetic acid was added dropwise under water cooling, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was concentrated under reduced pressure, 60rnl of ethyl acetate and 1Qrnl of water were added, the aqueous layer was separated, washed twice with ethyl acetate, and then washed with HP-20 (50rl).
nl) and eluted with 50% methanol, fractions containing the target compound were collected, concentrated under reduced pressure, and then lyophilized to obtain 70 mg (yield 6.3%) of the target compound. Melting point 146°C
(Disassembly).

IR(KBr):1765.1655.1600.15
10゜1ro40crn' NMR (D20) δ: 3.05~3.45 (6H,
m), 3. ．． 94 (6H1s), 4.10 (3H,
s), 5.481H%d, J=5.5), 5.97(I
H.

a, J=5.5), 6.90 (IH, s).

7.02(IH,s), 7.07(IH,s) Example 6 (A) Benzhydryl 7-C(Z)-2-methoxyimino-2-(2-)ditylaminothiazol-4-yl)
Acetamide-3-chloromethyl-3-cephem-4
-Carboxy L/-)1-oxide: Benzhydryl 7-((Z)-2-me)ximino-2
-(2-)Dithylaminothiazol-4-yl)acetamido-3-chloromethyl-3-cephem-4-carboxylate) 6 g (7°14 mmol) was dissolved in 60 ml of benzene, and under water cooling, methachloroperbenzoic acid was added. 1.
54 g (8.92 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with a 5% aqueous acidic sodium sulfite solution and saturated brine, dried over anhydrous sulfuric acid, and concentrated under reduced pressure to obtain an oil.

(B) Benzhydryl 7-1: (Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamide]-6-iodomethyl-6-cephem-
4-Carboxylate 1-oxide: Dissolve the oil obtained in (A) in 120 ml of acetone,
1.69 (10.7 mmol) of sodium iodide was added and stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate, followed by washing with a 5% aqueous sodium thiosulfate solution, water, and saturated brine.

After dehydration with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain an oily substance.

(C) Benzhydryl 7-1: (Z)-2-methoxyimino-2-(2-1 lytylaminothiazol-4-yl)acetamide: ]-5-(6,7-cyhydroxy-2
-Methyl-1,2,5,4-tetrahydro-2-inquinolinium) methyl-6-cephem-4-carboxylate 1-oxide iodo salt: 1/2 amount of the oil obtained in (B) Dissolved in dimethylformamide 30rILl, 6,7-cyhydroxy-2-
Methyl-1,2,3,4-tetrahytroinquinoline 9
After adding 00++tJ (5.03 mmol) and stirring at room temperature for 5 hours, the mixture was left in the refrigerator for 2 days.

The reaction solution was poured into ice water, extracted with methylene chloride, and washed six times with water, followed by successive washing with a 5% aqueous acidic sodium sulfite solution and saturated brine. After dehydrating the extract with anhydrous sodium sulfate, it was concentrated under reduced pressure for 1 ft.

The oily residue obtained was treated with diethyl ether to solidify, weighed several times, and dried to give 2.1 g of powder (yield 52.2%).
I got it.

(DJ Benzhydryl 7-[: (Z)-2-methoxyimino-2-(2-1 lytylaminothiazole-4-
yl)acetamide] -3-(6,7-cyhydroxy-2-methyl-1,2,3,4-tetrahydro-2-inquinolinium)methyl-6-cephem-4-carboxylate: Obtained in (C) 2.1 g (1.86 mmol) of the powder was dissolved in 40 TL of acetone, and 6.1 g of potassium iodide was added thereto.
9 (18.7 mmol) was added thereto, and 0.67 ml (9.42 mmol) of acetyl chloride was added dropwise at -30°C, followed by stirring at -20 to -10°C for 90 minutes. The reaction solution was added to an ice-cooled aqueous metabisulfite solution, and the precipitate was separated from P and washed with water. This precipitate was dissolved in methylene chloride, washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the obtained oily residue to solidify it. 1.5g powder (yield 72
．． 5%).

(E)7-C(Z)-2-(2-aminothiazole-4
-yl)-2-methoxyiminoacetamide]-3-(
6,7-cyhydroxy-2-methyl-1゜2.6.4-
Tetrahydro-2-inquinolinium) methyl-6-cephem-4-carboxylate: (1.59 (1.35 mmol) of the powder obtained in DJ was mixed with 15 ml of methylene chloride and 1.5 mA of 7=7-l!
3.8 mmol), trifluoroacetic acid 15- was added dropwise under water cooling, and the mixture was stirred at the same temperature for 2 hours.

The reaction solution was concentrated under reduced pressure, and 5Qm of ethyl acetate and 20% of water were added.
was added, the aqueous layer was separated and washed twice with ethyl acetate,
The solution was passed through HP-20 (50 m), followed by 150 mm of cold water, and the fractions containing the target compound were collected, concentrated under reduced pressure, and lyophilized to obtain 50 mm of the target compound (yield: 6.4%). Melting point 127℃
(Disassembly).

IR(KBr): 1765.1655.1610.1
525.1650.1280.1050crn-”NM
R(D,O)δ: 2.9-5.3 (6H,m), 5
．． 40 (I H, d, J = = 5.4), 5.90 (
IH・d, J=5.4), 6.72(IH,s), 6.
82(IH,s), 7.04(IH,s) Example 4 (A) Benzhydryl 7-C(Z)-2-methoxyimi/-2-(2-)ditylaminothiazol-4-yl)
Benzhydryl 7 −(:(Z>−2-methoxyimi/−
Tahenzhydryl obtained from 4 g (4° furimmol) of 2-(2-tritylaminothiazol-4-yl)acetamido-3-chloromethyl-6-cephem-4-carboxylate by carrying out the same operations as in Examples 2 and 3. 7-
[(Z) -2-Methoxyimino-2-(2-)ditylaminothiazol-4-yl)acetamido-3-iodomethyl-6-cephem-4-carboxylate 1-
Add 20ml of dimethylformamide to the oxide oil.
6,7-diacedoxy-2-methyl-1,2
, 3,4-tetrahytroinquinoline 2.2g (8,3
mmol) and stirred at room temperature for 5 hours. The reaction solution was poured into ice water, extracted with methylene chloride, and washed successively with water, 5% aqueous acidic sodium sulfite solution, and saturated brine. The extract was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the oily residue was treated with diethyl ether to solidify it, dried, and a powder of 4.9.9 (yield: 84.0%) was obtained. Ta.

(B) Benzhydryl 7-(:(Z)-2-methoxyimino-2-(2-)ditylaminothiazol-4-yl)acetamide)-5-(6,7-diacedoxy 2
-Methyl-1,2,3,4-tetrahydro-2-inquinolinium) methyl-3-cephem-4-carboxylate iodo salt: 4.9 g (4,0
mmol) was dissolved in 70ml of acetone, 8.71/(52.4 mmol) of potassium iodide was added thereto, and -3
After dropping 1.44 ml (20 mmol) of acetyl chloride at 0°C, the mixture was heated at -50 to -20°C for 30 minutes at -10°C.
Stirred at ~-8°C for 75 minutes. The reaction solution was added to 320 d of an aqueous solution containing 4.4 g of sodium metabisulfite, and the precipitate was separated and washed with water. This precipitate was dissolved in methylene chloride and washed with water, acidic sodium sulfite aqueous solution and saturated saline.

Diethyl ether was added to the oily residue obtained by dehydrating with anhydrous sulfuric acid (IJ) and concentrating under reduced pressure to solidify, and then dried to obtain powder 3.951 (yield: 62.7%).

NMR (CDC13) δ: 2.22 (9H1s), 2.
0-2.6 (2H, m), 2.4-5.4 (4H, m
).

5.98 (3H, s), 4.2-5.0 (4H.

m), 5.72 (IH, bd), 6.20 (IH, m)
, 6.70 (IH, s), 6.98 (IH, s), 6.
9-8.0 (28H.

m) (C)7- ((Z) -2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3
−? (6,7-diacedoxy-2-methyl-1゜2.3
．． 4-tetrahydro-2-inquinolinium)methyl-
3-cephem-4-carboxylate: 3.95 g of powder obtained in (B) (3,26 mm/L/
) with methine chloride/20ml and anisole 3.9mJ (
35.9 mmol), 20 d of trifluoroacetic acid was added dropwise under water cooling, and the mixture was stirred at the same temperature for 2 hours.

The reaction solution was concentrated under reduced pressure, and 30% of ethyl acetate and 60% of cold water were added.
Add 1rLl and separate the aqueous layer.

After washing twice with ethyl acetate, it was adsorbed on up-20 (70g), eluted with 50% methanol, and the fractions containing the target product were collected (concentrated under reduced pressure, then subjected to freeze-drying C-18).
By elution with 66% methanol, 50Tn9 of the target compound 18rn9 (yield 0.6%) and a mixture (1:1) containing the target compound were obtained.

Melting point: 154°C (decomposed).

IR(KBr): 1760.1610,1520.
1360.1210, 1175.1090°1030crn-” NMR (D, 0) δ: 2.38 (6H, s), 2.
9-3.5 (6H, m), 4.03 (3H, s), 5.
40 (IH,a, J=5.4), 5.92 (IH
1d%, T=5.4), 7.02(IH,s), 7.1
6(IH,s), 7.28(IH,s) Example 5 (A) Penthydryl 7-[:(Z)-2-methoxyimino-2-(2-)ditylaminothiazol-4-yl)acetamide ]-5-(6,7-diacedoxy1.
2,3.4-tetrahydro-2-inquinolin-2-yl)methyl-3-cephem-4-carboxylate 1-
Oxide: To 6,7-diacedoxy 1,2,3,4-tetrahytroinquinoline hydrobromide 7601n9 (2.24 mmol), add 20 ml of water and 20 ml of methylene chloride, and add hydrogen carbonate) IJ Neutralize with aluminum powder, separate the organic phase, add anhydrous sulfuric acid, and dry with IJum.

A methylene chloride solution containing 6,7-diacedoxy 1,2,3,4-tetrahytroinquinoline was prepared. Penthydryl 7-C(Z)-2-methoxyimino-2-(2-)ditylaminothiazole-4 was added to this amine solution.
-yl)acetamido-6-iodomethyl-3-cephem-4-carboxylate 1-oxide 1.129
(1.18 mmol) was added and stirred at room temperature for 1 hour.

After methylene chloride was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (methylene chloride→2% methanol-methylene chloride) to obtain amorphous powder 836× (yield 98%).

NMR (CDCl, )δ: 2.23 (6H,S), 2
．． 4-2.9 (4H, m), 3.12 (IH, d, J=
18), 5.2-3.5 (4H, m), 4.04 (
3H%S), 4.05 (IH, a, , r=18), 4.
42 (IH,a, J=s), 6.08 (IH,aa
, J=5.11), 6.68(IH,s), 6.72
(IH, s), 6.85 (1, H, s), 6.96 (I
H.

s), 7.1-7.8 (25H, m) (B) Penthydryl 7-((Zl-2-methoxyimi/-2-(2-tritylaminothiazol-4-yl)
acetamido)-3-(6,7-diacedoxy-2-methyl-1,2,3,4-tetrahydro-2-quinolinium)methyl-3-cephem-4-carboxylate 1-oxide iodo salt: ( 817 ml (0, mmol of fluorofluoride) of the amorphous powder obtained in A) was dissolved in 8.2 ml (132 mmol) of methyl iodide and left at room temperature in the dark for 6 days. The reaction solution was subjected to silica gel column chromatography (methylene chloride → 2% methanol in methylene chloride → 4% methanol/methylene chloride) to obtain a powder of the title compound 470rn9 (yield 51%).
) was obtained.

The NMR-spectrum and thin layer chromatography of this product were consistent with the compound obtained in Example 4(A).

Example 6 7-((Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(6,
7-hydroxy-2-methyl-1,2゜3.4-tetrahydro-2-isoquinolinium)methyl-3-cephem-4-carboxylate: 2.5 m9 of the compound obtained in Example 4(C) was dissolved in methanol 0. .5 ml of the suspension, 35 μl of concentrated ammonia water was added, and the mixture was left at room temperature for 1 hour. The reaction solution was converted into HPLCl: Develosil 0D
S-5 (10X 250mrtt), THF-H2O
(15:85)), the raw material peak RJ=
9.6 min disappeared, showing the same Rt = 8.0 min as the compound obtained in Example 6(E). This peak was collected and lyophilized to obtain 1m9 of the title compound.

This is bioautography CTLC: Merck silica gel F254, CH, CN: C2H,0COC
H,: H,0 (3: 1: 1).

In E coli NIHJ:l, Rf = 0
．． 1 shows a spot exhibiting antibacterial properties, which coincided with the antibacterial spot of the compound of Example 3(E). Note that the antibacterial spot of the raw material had Rf=0.4. Also, this is Example 3
It showed the same antibacterial spectrum as compound (E).

Example 7 (A) Benzhydryl 7-1: (Z)-2-ethoxyimino-2-(2-)ditylaminothiazol-4-yl)acetamide]-6-chloromethyl-6-cephem-
4-Carboxylene) 1-4oxide: Benzhydryl 7-[:(Z)-2-ethoxyimino-
2-(2-tritylaminothiazol-4-yl)acetamido-6-chloromethane-3-cephem-4-carboxylate4. Ofj (4.7 mmol) was dissolved in 40 ml of benzene, and while cooling with water, 4 mmol of methachloroperbenzoic acid (i, o gc s, a mmol) was added at room temperature.
Stirred for 0 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with 5% acidic sulfite, washed with an aqueous solution of IJ and saturated brine, then dried with sulfuric acid, and concentrated under reduced pressure to leave an oily residue. Add n-hexane to the mixture, solidify it, dry it and make the powder of the title compound &8
g (yield 93%) was obtained.

IR(KBr): 1800.1720.1680,
1040.7QQcrn-' NMR (DMSOda) δ: 1.0-1.40 (
SH,m), 3.30 (2H,s), 3.70-4.
20 (4H, m), 4.30-4.70 (2H.

m), 5.05 (IH, m), 5.90 (IH, m),
6.80 (IH, s).

7.00 (IH,s), 7.10-7.70 (
25H,m), 8.75(IH,m)(B) Benzhydryl 7-[:(Z)-2-ethoxyimino-2-(2-
tritylaminothiazol-4-yl)acetamide]
-3-(2-methyl-1,2,3,4-tetrahydro-
(2-Inquinolinium) Methyl-6-cephem-4-carboxylate 1-oxide iodo salt: 1.44.9 mL of sodium iodide in 601 nL of acetone (
After stirring for 10 minutes under water cooling, 3.8 g (4.4 mmol) of the powder obtained in step 1) was added and stirred for 15 minutes. After concentrating the reaction solution under reduced pressure,
Ice water and ethyl acetate were added, and the organic layer was separated. The organic layer was washed successively with 5% acidic sodium sulfite aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain an oily 6-iodomethyl compound. To this 6-iodomethyl form, dimethylformamide 15 mA' and 2-methyl-1,2,3,4-tetrahytroinquinoline 1,
19 (7.5 mmol) was added and stirred at room temperature for 40 minutes. The reaction solution was poured into ice water, extracted with methylene chloride, and washed successively with water, 5% aqueous acidic sodium sulfite solution, and saturated brine. The extract was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting oily residue was treated with diethyl ether to obtain 4 g of powder. This powder was purified by flash silica gel column chromatography (methylene chloride:methanol=20:1) to obtain a powder containing 1.69 diastereomer mixtures of the title compound (yield: 66.5%).

IR(KBr): 1800.1720.1670.1
220°1030.750.700Crn-1 NMR (DMSO-d,; ) δ: 1.0-1.35
(6H1m >, 4.13 (2H, (1, J=6
), 5.17 (IH, m), 6.06 (IH, m), 6
・78 (IHLs), 6.92 (IHLs), 10
0-7.70 (29ze%m), 8.70 (IH.

S), 8.95 (I H, d, , T=7.5) (
C>Benzhydryl 7-1: (Z>-2-ethoxyimino-2-(2-)ditylaminotheazol-4-yl)
acetamido)-3-(2-methyl-1,2,3,4-
Tetrahydro-2-inquinolinium) methyl-6-cephem-4-carboxylate iodo salt: Dissolve the powder 1.6.9 (1,46 mmol) obtained in (B) in acetone 40, and add to it. Potassium iodide 2.4g
(14.4 mmol) was added, and 0.5"5 at (7.7 mmol) of acetyl chloride was added dropwise at -30°C. Stirred for 5 hours.The reaction solution was added to an ice-cooled aqueous sodium metabisulfite solution, and the precipitate was washed with water.The precipitate was dissolved in methylene chloride, washed with saturated brine, and then dehydrated with anhydrous sodium sulfate. Ether was added to the oily residue obtained by concentrating under reduced pressure to solidify it, and P was removed.

Dry to give a diastereomeric mixture of the title compound 1,49
(Yield: 88.7%) powder was obtained.

IR(KBr): 1780.1720.1670.
1220.1030.750.7Q[1crn-'NM
R(DMso-da)δ: 1.0 to 1.40 (3
H,m), 4.0-4.9.0 (8H,m),
5.43 (IH.

m), 5.93 (IH, m), 6.80 (IH, s),
6.95 (IH, s), 7.0-7.70 (29H, m
), 9'60 (1H, m) (D) 7- [(Z) -2
-(2-7minothiazol-4-yl)-2-ethoxyiminoacetamide]-5-(2-methyl-1,2,
3,4-Tetrahydro-2-inquinolinium) methyl-6-7femu-4-carboxylate: 1.57 g (1.27 mmol) of the powder obtained in (C) was added to 10 ml of methylene chloride and 1.3 ml of anisole. Dissolve.

While cooling with water, add 9 ml of trifluoroacetic acid dropwise at the same temperature.
Stir for hours. The reaction solution was concentrated under reduced pressure and 1Qm of ethyl acetate was added.
After adding 100 g of ice water and separating the aqueous layer and washing it with ethyl acetate, it was adsorbed on HP-20 (150 mJ).
The eluate was washed until it became neutral. Next, 50% methanol was passed through.

Fractions containing the target product were collected, concentrated under reduced pressure, and freeze-dried to obtain 340 m9 of the target product (yield: 50.4%).

Melting point 159°C (decomposition).

IR(KBr):1770.1610.1560.10
30crn-'NMR (DCI-D20) δ: 1.3
0 (3H, t, J=7.0), 2.95-3.50 (
7H,m), 4.30 (2H%q, J=ZQ), 5.
55 (IH.

d,, T=4.5), 5.80 (IH, m), 7.05
(IH, s), 7.10-7.40 (4H, m) Example 8 (A) Benzhydryl 7 [(Z) 2- (
1-1ert-butoxycarbonyl-1-methylethoxyimino)-2-(2-tritylaminothiazole-4
-yl) acetamidocou 3-chloromethyl-3-cephem-4-carboxylate 1-oxide: benhydryl 7-[:(z) 2- (1-ter
t-butoxycarbonyl-1-methylethoxyimino)
-2-(2-1 lytylaminothiazol-4-yl)acetamide]-6-chloromethyl-6-cephem-4-
Carboxylate 10,p (10.3 mmol) was dissolved in 20 rJml of methylene chloride, and methachloroperbenzoic acid 1.789 (10.6 mmol) was added over 10 minutes while cooling with water, followed by stirring for an additional 20 minutes. After adding 40 mA' of 10% aqueous sodium thiosulfate solution to the reaction solution and separating the layers, the organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound in powder form.

IR (KBr): 1795.1720.1680.
1500.1665.1600.1250.1170.
1140.1050crn-' NMR (DMSO-d,) δ: 1.36 (9H, s),
1.45 (6H1S), 6.9 (2H,m), 4.
55 (2H, m), 5.1 (1HSd, J=5)
, 6.0 (jH, da.

J=5 & 9 ), 6.8 (IH,s ), 7.0 (I
H.

S), 7.6 (25H, brs), 8.15 (IH.

dSJ=9 ), 8.7 (IH, S ) (B) Benzhydryl 7 ((Z) 2 (1-tert
-Ptoxycarbonyl-1-methylethoxyimino')
-2-C'), -) The compound obtained by lythylaminothiazole (A) was dissolved in 200 mJ of acetone, 3.68 IC22.5 mmol of sodium iodide was added, and the mixture was heated to 30 mJ at room temperature.
Stir for a minute. After adding 600 ml of cold ethyl acetate and 200 rnl of cold 10% sodium thiosulfate solution to the reaction solution and separating the layers, the organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. - Separation and purification with hexane 1:2). After collecting and concentrating the fractions containing the target compound, diisopropyl ether was added to the residue to obtain the title compound 7 in powder form.
．． 09 (yield 63.0%) was collected.

IR(KBr): 1795.1720,1680,1
500°1670.1600.1250.1170°1
140.1050crn"-' NMR (DMSO-d,) δ: 1i5(9H,a), 1
．． 45 (6H.

S), 3.95 (2H, m), 4.45 (2H, m)
, 5.1 (IH,a, J=5), 6.0 (I
H, dd.

J = 5&9), 6.8 (iH,s), 7.0
(IH.

S) 1.7.3 (25H, brs), 8.15 (IH1
dSJ=9), 8.7 (IH,s)(C)benzhidori/I/7-C(Z)-2-(1-t, ert.

-butoxycarbonyl-1-methylethoxyimine/)-
2-(2-)ditylaminothiazol-4-yl)acetamide: l-3-(2-methyl-1,2,3,4-tetrahydro-2-inquinolinium)methyl-3-cephem-4-carboxy Rate 1-oxide iodo salt: Compound 217 (1,86 mmol) obtained in (B) was dissolved in 50 wLl of ethyl acetate, and 2-methyl-1,2+
3.4-tetrahydroisoquinoline 5001n9 (2,
After adding 0.04 mmol), the mixture was stirred at room temperature for 6 hours.

The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel flash column chromatography (2-6% methanol-methylene chloride). Fractions containing the target product were collected and concentrated to obtain 1.20 g of the title compound in powder form (yield). 52.8%).

(D) Benzhydryl 7 C(Z) 2 (1-
t,ert.

-butoxycarbonyl-1-methylethoxyimino)-
2-(2-)ditylaminothiazol-4-yl)acetamide]-3-(2-methyl-1,2,!t,4-tetrahydro-2-inquinolinium)methyl-3-cephem-4-carboxylate・Iodo salt: 1.209 (0.98 mmol) of the compound obtained in (C)
and 301 nl of acetone to 810 μm (4.88 mmol) of potassium iodide! was added, and 0.17 ml ('2.69 mmol) of acetyl chloride was added dropwise at -20'C. After stirring for 2 hours at -20 to -10°C, 810 ml of potassium iodide and 0.1 ml of acetyl chloride were added. Add 17m,
The mixture was further stirred at the same temperature for 1.5 hours. 100 ml of methylene chloride and 100 mA' of 1% aqueous sodium metabisulfite solution-saturated saline (1:1) were added to the reaction solution, and the organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound in powder form. Ta.

IR(KBr):1785.1720.1360.12
50゜1220.1140crr1-' (E)7-[(Z)-2-(2-aminothiazole-4
-yl)-2-(1-carboxy-1-methylethoxyimino)acetamide)-3-(2-methyl-1,2,
3,4-tetrahydro-2-inquinolinium) methyl-3-cephem-4-carboxylate: The compound obtained in (D) was dissolved in 12 ml of methylene chloride, 1.2 ml of anisole was added, and the mixture was cooled with water. After adding 12 ml of trifluoroacetic acid and stirring at the same temperature for 6 hours,
The solvent was distilled off under reduced pressure. 20 ml of ethyl acetate was added to the residual solution, and the mixture was concentrated under reduced pressure. After repeating this operation twice,
New ethyl acetate 150mA! and 100 g of water were added to separate the liquids. The organic layer was further added with 1.00 ml of water, combined with the aqueous layer, washed with 50 ml of ethyl acetate, the dissolved organic solvent was removed under reduced pressure, and the organic layer was subjected to reverse phase chromatography (Waters PrePack 500/C-18).
40 ml) for separation and purification (200 ml of H2O and 4%
After removing the organic solvent under reduced pressure, the aqueous tetrahydrofuran solution 4QQmA')1 was freeze-dried to obtain diastereomers A and B of the title compound.

Compound A 42■ (yield 7.0%) Melting point = 168°C (decomposition) IR (KBr): 1775.1660.1610.1
530.1350.1190.1160crn''NMR
(DMS o-d,) δ: 1.45 (6H, brs
), 2.95 (3H, brs), 5.2 (IH, d,
J=5 ), 5.75 (IHlad, , r=5&
9), 7.6 (4H, brs), 9.5 (IH, d
, J=9) Compound B 78Tn9 (yield 12.9%
) Melting point = 140°C (decomposition) IR (KBr): 1775.1660.1610.
15i.

1340.1185.1155cm'' NMR (DMSO-d6) δ: 1.45 (6H, br
s), 2.95 (5H.

brs), 5.2 (IH, a, J=5), 5.
75 (IH, aa, , r=5&9), 7.3 (4H
.

brs), 9.45 (IHla, J=9) High performance liquid chromatography column: Develosil 0DS-5 (10X
250 m) Mobile phase: 15% aqueous tetrahydrofuran solution Flow rate: 2 m 11 minutes Detection: UV 254 nm Retention time Compound A: 5.5 minutes Compound B: 6.5 minutes Compounds of Examples 9 to 13 were obtained in the same manner as in Example 2. Ta.

Example 9 7-((Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(6-
Acetoxy-2-methyl-1,2,3,4=tetrahydro-2-inquinolinium) methyl-3-7-phe, mu-4-carboxylate (mixture of diastereomers A and B): Melting point = 154°C (decomposition ) IR (KBr): 1780.1670.1620.
1540.1380.1220crn-1 HMR (DMSO-d, )δ: 2.25 (3H%S)
, 2.8-4.7 (1sa, m), 3.85 (3H, s
), 5.15 (I H, d, J=5Hz), 5.6
7 (IH.

dd, J = 5 and 7 Hz), 6.73 (IH, s
), 7, 0-7.3 (5H1m), 9.50 (I
H, a.

J=7H2) Example 10 7-C(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-6-(6-hydroxy-2-methyl-1,2,3 ,4-tetrahydro-2-inquinolinium)methyl-3-cephem-4-
Carboxylate (mixture of diastereomers A and B): Melting point: 175°C (decomposed) IR (KBr): 1780.1680.1620.
1540cr11-NMR (DMSO-d,) δ: 2.
8-4.6 (j6H, m), 5.15 (I H, d
, J=5 Hz), 5.67 (IH.

dd, J = 5 and 9 Hz), 6.63 (IH, s)
, 6.70 (IH, s), 7.20 (2H, brs)
, 9.55 (IH,a, J=9) Example 11 7-((Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(5,
6-hydroxy-2-methyl-1,2°3.4-tetrahydro-2-inquinolinium)methyl-6-cephem-4-carboxylate (diastereomer A, B mixture): Melting point = 166°C (decomposed) IR(KBr): 1780.1680,1620.
1200.1140.1050crrI'' NMR (DMS O-d, )δ: 2.96 (3H
, brs), 3.2-4.9 (13H, m), 5.2
9 (IH, d, J=5Hz), 5.87 (1H,
d, J=5 and 9Hz), 6.45 (IH, m),
6.73 (IH, S), 6.9-7.3 (2H%m)
, 9.60 (IH, d.

J=9Hz) Example 12 7-((Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(2-methyl-1,2,3,4-tetrahydro -6,7,8-)
dihydroxy-2-inquinolinium) methyl-6-cephem-4-carboxylate (diastereomer A,
B mixture): Melting point = 182°C (decomposition) IR (KBr): 1780.1670.1620.
1540.1480cr11-1 NMR (DMSO-d6) δ: 2.6-4.5 (1
6H, m), 5.17 (IH, m), 5.68 (IH
, m), 6.20 (IH, s), 6.73 (IH, s)
, Z20 (2H, brs), 9.55 (IHld,
J = 9Hz) Example 13 7-[(Z)-2-(2-aminothiazol-4-yl)-2-isopropoxyiminoacetamide)-3-(
6,7-cyhydroxy-2-methyl-1,2,3,4-
Tetrahydro-2-isoquinolinium) methyl-3-cephem-4-carboxylate (diastereomer A,
B mixture): Melting point = 174°C (decomposition) IR (KBr): 1780.1620.1540.
1390.1360crrI-' NMR (DMSO-d6) δ: 1.23 (6H, d
, J=6Hz), 2.90 (6H,brs),
3.0-4.6 (11H.

m), 5.17 (IH, d, J = 5Hz), 5.
67 (IH, dd, J=5 and 9Hz), 6.51 (
IH, S), 6.63 (IH, s), 6.70 (IH,
s), 7.20 (2H, brs), 9.45 (1H,
d, J=9Hz) Example 14 (A) Penthydryl 7-((Z)-2-(penthydryloxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamidocou 3-chloro Methyl-3-cephem-4-carboxylate 1-oxide: penthydryl 7-C(Z)-2-
(benzhydryloxycarbonylmethoxydiimino)
-2-(2-tritylaminothiazol-4-yl)acetamidocou-3-chloromethyl-3-cephem-4-
Calfoxyle) 23.4,! 9 (22.3 mmol) was dissolved in 500 mJ of methylene chloride, and 4.8 g (22.3 mmol) of methachloroperbenzoic acid was dissolved under water cooling.
The mixture was added for 0 minutes and stirred for an additional 20 minutes. 10% to reaction solution
Sodium thiosulfate aqueous solution 15C11A! After adding and separating the organic layer, the organic layer was washed with a 5% aqueous sodium bicarbonate solution, dehydrated with anhydrous sulfuric acid, and concentrated under reduced pressure to obtain the title compound in powder form. This was used in the next reaction without purification.

IR (KBr): 1800.1730.1680.
1520.1490.1450.1375.1250.
1180.1090.1060.1010, (B) Iodomethyl-3-cephem-4-carboxylate 1-oxide: (The compound obtained with Al was mixed with acetone at 380 mA!
7.417 (49 mmol) of sodium iodide was added thereto, and the mixture was stirred at room temperature at 50 fat. Add 600 liters of 10% sodium thiosulfate aqueous solution and 1150 liters of ethyl acetate to the reaction solution.
The organic layer was dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (ethyl acetate/n-hexane = 1
:1) to obtain 22.4p of the title compound in powder form (
A yield of 86.7% from the previous step was obtained.

IR (KBr): 1795.1725.1685.
1520.1495.1450.1370.1290.
1260.1180.1085.1060.750.7
Q Q cm-' NMR (pMso-a6): 3.9 (2H, br
s ), 4.5 (2E(,m), 4.9 (2H,b
rs), 5.08 (IH, d, J=5Hz), 5.
93 (IHSdd, J=5 and 8Hz), 6.87 (
IH,s), 6.92 (IH.

S), 7.0 (IHSs), :15 (36a.

m), 8.85 (2H, m) (C) Benzhydryl 7-((Z)-2-(benzhydryloxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-
3-(6,7-cyhydroxy-1.2,3.4-tetrahytroinquinolin-2-yl)methyl-3-cephem-4-carboxylate 1-oxide: 4 g of the compound obtained in (B) (3, 4 mmol) and 6,7
-cyhydroxy-1.2.3.4-tetrahydroisoquinoline hydrobromide 1.27 F (5.2 mmol) was dissolved in 15 mmol of dimethylformamide and triethylamine 0.717 d (5.1 mmol) was dissolved at room temperature. IJ mol) was added thereto, and the mixture was stirred at the same temperature for 2 hours. Concentrate the reaction solution under reduced pressure,
The residue was purified by silica gel column chromatography (2% methanol/chloroform) to obtain the title compound 6.5,
! i' (yield 84%) was obtained.

Engineering R (KBr): 1800.1740.1660.
1560crrr4NMR (DMS O-d,) δ:
2.6-2.7 (4H, m), 3.0-3.5 (s
a, m), 4.37 (IH, d, J = 6.0Hz
), 4.87 (2H, brs ), 6.03 (IH,
m), 6.60 (IH, s), 6.47 (IH, s),
6.70 (IH%s), 6.88 (IH,s), 6.9
5 (IH, s), 7.1-7.5 (35H, m), (D
) Benzhydryl 7-((Z) -2-(benzhydryloxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-3
-(6,7-cyhydroxy-2-methyl-1,2,3,
4-tetrahydroinquinolinium) methyl-6-cephem-4-carboxylate 1-oxide iodo salt: 6.5 g of the compound obtained in (C) was mixed with methyl iodide 20FM (
621 mmol) and stirred at room temperature for 15 hours.

The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2-5% methanol/chloroform) to obtain the title compound 2.7.9 (yield 69%).

IR (KBr): 1800.1690.1640.
1620.153 Don-' NMR (DMSO-d, ) δ: 2.6-5.0 (
AH, m), 3.0-3.7 (6H, m), 3.9-
4.5 (4H, m), 4.8! l (2H,br
s), 5.40 (In, a.

J = 4.5Hz), 5.93 (IH, m), 6.47 (
IH, s), 6.61 (1H, s), 6.77 (IH,
S), 6.88 (IH, s), 71-7.6 (55HS
m) (E) Benzhydryl 7-((Z)-2-(benzhydryloxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-
3-(6,7-cyhydroxy-2-methyl-1,2,3
, 4-tetrahydroisoquinolinium) methyl-6-cephem-4-carboxylate Φ iodo salt: Compound 2.7f obtained in (D)! (2,0 mlJ mole) Rough 7 tons 50mA! dissolved in potassium iodide 3.35
g (20.2 mmol), then 0.72 ml (10 mmol) of ayacha chloride was added at -20'C, and the mixture was stirred at -20'C for 60 minutes and at -10°C for 3.5 hours. . The reaction solution was poured into a 2% aqueous sodium metabisulfite solution, and the precipitate was collected.

This precipitate was dissolved in chloroform, washed with saturated brine, and then dehydrated with anhydrous sodium sulfate. The title compound 2.317 (yield 86%) was obtained by distilling off the solvent under reduced pressure.

NMR (DMSO-d, )δ: 2.6-2.9 (
3H,m), 5.1~3.8 (6HSm), 4.0~
4.6 (4H1m), 5.17 (IH, m), 6.
07 (IH, m), 6.43 (IH, s), 6.6
0 (IH, s), 6.85 (IH, s), 6.88 (
IH,s), 7.1-7.6 (35H,m) (F) 7-C(z)-2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamide]-5- (6,7-cyhydroxy-2-methyl-
1,2,3,4-tetrahydro-2-isoquinolinium)methyl-3-cephem-4-carboxylate (mixture of diastereomers A and B): Compound 2 obtained in (E)
．． 2 Il (1,66 mmol) in methylene chloride 1Qm
l and anisole 2.2 m1. 15 mJ of trifluoroacetic acid was added dropwise under water cooling, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the residue.
The aqueous layer was subjected to reverse phase chromatography (Water PrePa
The product was purified using cK 500/C-18 (2% tetrahydrofuran/water), and fractions containing the target compound were collected and lyophilized to obtain the title compound 180 ml (yield 17.5%).

Melting point = 179°C (decomposition) IR (KBr): 1780.1620.1540.
1690.1360.1280 cm-” NMR (DMSo-d6) δ: 2.93 (5H,b
rs), 3.0-4.7 (10H, m), 4.57
(2H, brs), 5.60 (2H, brs), 5.
20 (IH, d.

J = 5H2), 5.53 (IH, s), 5.73 (IH
Sm), 6.63 (IH, s), 6.83 (IH, s)
, 7.23 (2H, brs), 9.80 (1H1d%J
= 9 Hz) Example 15 In the same manner as in Example 14, 7-((Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1
-methylethoxyimino)acetamide)-3-(6,
7-hydroxy-2-methyl-1,2,3,4-tetrahydro-2-inquinolinium)methyl-3-cephem-4-carboxylate (diastereomer A, B mixture) was obtained.

Melting point: 184°C (decomposed) IR (KBr): 1780.1620.1540.
1690.1360.1280.1200.1160c
bNMR (nuso-a6) J: t 50 (6
H%s), 2.93 (3Lbrs), 3.0-4
．． 7 (10H, m), 5.22 (IH, d, J
=5Hz), 5.75 (IH.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 is a linear or branched lower alkyl group which may be substituted with a carboxyl group, R^2, R^
3 and R^4 may be the same or different and each represents a hydrogen atom, a hydroxyl group, a methoxy group, or an acetoxy group), a salt thereof, or a physiologically hydrolyzable ester thereof. 2. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R^5 is a hydrogen atom or an amino protecting group, R^6 is a hydrogen atom or a carboxyl protecting group, and R^7 is a protected carboxyl a linear or branched lower alkyl group which may be substituted with a group, X is a halogen atom or a leaving group,
Y represents S or SO), or its salt, with the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R^8, R^9 and R^1^0 are the same but may be different, each represented by a hydrogen atom, an optionally protected hydroxyl group, a methoxy group, or an acetoxy group; There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R^5, R^6, R^7, R^8, R^9, R^
1^0, R^1^1 and Y have the above meanings, X^■
represents an anion), which is methylated and/or reduced as necessary, and then the protective group is removed. There are general formulas, mathematical formulas, chemical formulas, tables, etc. ▼(I) (In the formula, R^1 is a linear or branched lower alkyl group that may be substituted with a carboxyl group, R^2, R^
3 and R^4 may be the same or different and each represents a hydrogen atom, a hydroxyl group, a methoxy group, or an acetoxy group), a salt thereof, or a method for producing a physiologically hydrolyzable ester thereof. 3. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) (In the formula, R^6 is a hydrogen atom or a carboxyl protecting group, R^
8, R^9 and R^1^0 may be the same or different,
A compound represented by a hydrogen atom, an optionally protected hydroxyl group, a methoxy group or an acetoxy group, a salt thereof or a silyl compound thereof, respectively, is represented by the general formula ▲ mathematical formula, chemical formula, table, etc. ▼(VI) (In the formula, R^5 is a hydrogen atom or an amino protecting group, and R^7 is a linear or branched lower alkyl group which may be substituted with a protected carboxyl group.) Acylated with reactive derivatives of carboxylic acids, the general formula ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ (VII) (wherein R^5, R^6, R^7, R^8, R^9, R^
There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (I) (formula R^1 is a linear or branched lower alkyl group which may be substituted with a carboxyl group, R^2, R^
3 and R^4 may be the same or different and each represents a hydrogen atom, a hydroxyl group, a methoxy group, or an acetoxy group), a salt thereof, or a method for producing a physiologically hydrolyzable ester thereof. 4. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 is a linear or branched lower alkyl group that may be substituted with a carboxyl group, R^2, R^
3 and R^4 may be the same or different and each represents a hydrogen atom, a hydroxyl group, a methoxy group, or an acetoxy group), a salt thereof, or a physiologically hydrolyzable ester thereof, as an active ingredient. Antibacterial agent.